1.1 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

XACDURO is indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of XACDURO and other antibacterial drugs, XACDURO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2.1 Recommended Dosage

XACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. The recommended dosage of XACDURO is 1 gram (g) of sulbactam and 1 g of durlobactam every 6 hours administered by intravenous (IV) infusion over 3 hours in adults with a creatinine clearance (CLcr) of 45 to 129 mL/min.

Adjustments to the dosing regimen for XACDURO are recommended for patients with CLcr less than 45 mL/min and for patients with CLcr greater than or equal to 130 mL/min [see Dosage and Administration (2.2)].

The recommended duration of treatment with XACDURO is 7 to 14 days. The duration of therapy should be guided by the patient's clinical status.

2.2 Dosage in Patients (18 Years of Age and Older) Based on Renal Function

See Table 1 for the recommended dosage of XACDURO in patients (18 years of age and older) based on renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Adjustments to the dosing regimen are recommended for patients with creatinine clearance (CLcr) less than 45 mL/min and patients with augmented renal clearance (CLcr greater than or equal to 130 mL/min). For patients undergoing intermittent hemodialysis (HD), start the dosing of XACDURO immediately after the completion of HD.

For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly [see Use in Specific Populations (8.6)].

2.3 Administration

The prepared XACDURO solution [see Dosage and Administration (2.4)] should be brought to ambient room temperature (over 15 to 30 min) prior to infusion to the patient. Administer all doses of XACDURO by intravenous (IV) infusion over 3 hours.

2.4 Preparation of XACDURO for Intravenous Administration

XACDURO is a co-packaged kit containing 1 clear single-dose vial of sulbactam 1g and 2 amber single-dose vials of durlobactam 0.5g as sterile powders that must be reconstituted and further diluted using aseptic technique prior to intravenous infusion.

XACDURO does not contain a bacteriostatic preservative and the prepared solution must be used within 24 hours when stored refrigerated at 2°C to 8°C (36°F to 46°F). Discard unused portion.

2.5 Compatibility

XACDURO is compatible with 0.9% Sodium Chloride Injection, USP.

The compatibility of XACDURO for administration with solutions containing other drugs or other diluents has not been established. XACDURO should not be mixed with other drugs or physically added to solutions containing other drugs.

2.6 Storage of Prepared Solution in Infusion Bag

Store the prepared bag in the refrigerator at 2°C to 8°C (36°F to 46°F) until administration. The time between starting the reconstitution of the powders and the conclusion of the infusion should not exceed 24 hours. Do not freeze.

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. Hypersensitivity was observed in patients treated with XACDURO in clinical trials [see Adverse Reactions (6.1)]. Before initiating therapy with XACDURO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. Discontinue XACDURO if an allergic reaction occurs.

5.2 Clostridioides difficile-Associated Diarrhea (CDAD)

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XACDURO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, the risk/benefit of continuing treatment with XACDURO should be assessed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.3 Development of Drug-Resistant Bacteria

Prescribing XACDURO in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6.1 Clinical Trials Experience

Clinical trials are conducted under widely varying conditions, therefore adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of durlobactam with or without sulbactam was evaluated in 380 adult subjects across six phase 1 trials, one phase 2 trial in patients with complicated urinary tract infections (cUTIs) including acute pyelonephritis, and one phase 3 trial (also referred to as Trial 1) in adult patients with infections caused by Acinetobacter baumannii-calcoaceticus complex including hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and ventilated pneumonia (VP) [see Clinical Studies (14)].

In the randomized, active-controlled portion of the phase 3 trial, 91 patients received XACDURO (1 g sulbactam and 1 g durlobactam, or renally adjusted dose) intravenously over 3 hours every 6 hours and 86 patients were treated with colistin 2.5 mg/kg (or renally adjusted dose) intravenously over 30 minutes every 12 hours after an initial loading dose of colistin 2.5 to 5 mg/kg. Both treatment arms also received 1 g imipenem/1 g cilastatin (or renally adjusted dose) intravenously every 6 hours as background therapy for potential HABP/VABP pathogens other than Acinetobacter baumannii-calcoaceticus complex. The mean duration of XACDURO therapy was 9 days versus 8 days for colistin.

7.1 Organic Anion Transporter 1 (OAT1) Inhibitors

Concomitant administration with OAT1 inhibitors may increase plasma concentrations of sulbactam. Concomitant administration of OAT1 inhibitors (e.g., probenecid) with XACDURO is not recommended. [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of XACDURO in pediatric patients younger than 18 years of age have not been established.

8.5 Geriatric Use

Of the 91 patients treated with XACDURO in Trial 1, 49 (54%) were 65 years of age and older, including 17 (19%) patients 76 years of age and older. Clinical studies of XACDURO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

XACDURO is known to be substantially excreted by the kidney and elderly patients are more likely to have decreased renal function. Adjust dosing regimen for elderly patients based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

8.7 Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of sulbactam and durlobactam have not been evaluated. Hepatic impairment is not expected to alter the elimination of XACDURO as neither sulbactam nor durlobactam undergo substantial hepatic metabolism/excretion. Dosage adjustments are not necessary in patients with impaired hepatic function.

Sulbactam Sodium

Sulbactam sodium is a beta-lactam antibacterial and a beta-lactamase inhibitor. Chemically, sulbactam sodium is sodium penicillinate sulfone; sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide. Sulbactam is a white to off-white crystalline powder that is freely soluble in water and its empirical formula is C8H10NNaO5S with a molecular weight of 255.22.

Figure 1: Chemical structure of sulbactam sodium

Durlobactam Sodium

Durlobactam is a beta-lactamase inhibitor antibacterial drug. Chemically, durlobactam sodium is sodium (2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate. Durlobactam sodium is the pure (2S,5R)-enantiomer of the trans diastereoisomer. It is a white to yellow amorphous powder that is freely soluble in water. The empirical formula is C8H10N3NaO6S and the molecular weight (sodium salt) is 299.23.

Figure 2: Chemical structure of durlobactam sodium

XACDURO is supplied as a co-packaged kit containing three single-dose vials each containing sterile powder for reconstitution: one clear single-dose vial contains 1 g sulbactam (equivalent to 1.1 g sulbactam sodium) and two amber single-dose vials each contain 0.5 g durlobactam (equivalent to 0.54 g durlobactam sodium) together with sodium hydroxide and hydrochloric acid used for pH adjustment.

12.1 Mechanism of Action

XACDURO is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

For sulbactam, the percent time of dosing interval that unbound plasma concentrations of sulbactam exceed the minimum inhibitory concentration (MIC) of A. baumannii has been shown to be the best predictor of efficacy in animal and in vitro models of infection. For durlobactam, the ratio of the 24-hour unbound plasma durlobactam AUC to the sulbactam-durlobactam MIC (fAUC0–24/MIC) best predicts the activity in in vivo and in vitro models of infection.

12.3 Pharmacokinetics

Sulbactam and durlobactam pharmacokinetics are similar following single- and multiple-dose administrations. The Cmax and AUC of sulbactam increase in proportion to dose (0.5 times the recommended single dose to 1 g single dose). Durlobactam demonstrated dose-proportional pharmacokinetics across the dose range studied (0.25 times the recommended single dose to 2 times the recommended single dose infused over 3 hours every 6 hours).

The pharmacokinetic properties of the components of XACDURO and the pharmacokinetic parameters of sulbactam and durlobactam are summarized in Table 3.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Treatment of Hospital-acquired and Ventilator-associated Bacterial Pneumonia Caused by Acinetobacter baumannii-calcoaceticus Complex Organisms

A total of 177 hospitalized adults with documented Acinetobacter baumannii-calcoaceticus complex infections were randomized and treated in a multicenter, active-controlled, investigator-unblinded, independent assessor-blinded, non-inferiority, phase 3 trial (Trial 1, NCT03894046). Patients were treated with either XACDURO (1 g sulbactam and 1 g durlobactam, or renally adjusted dose) intravenously over 3 hours every 6 hours (n = 91) or colistin 2.5 mg/kg (or renally adjusted dose) intravenously over 30 minutes every 12 hours after an initial loading dose of colistin 2.5 to 5 mg/kg (n = 86). Both treatment arms also received 1 g imipenem/1 g cilastatin (or renally adjusted dose) intravenously every 6 hours as background therapy for potential HABP/VABP pathogens other than Acinetobacter baumannii-calcoaceticus complex. Patients received up to 14 days of therapy.

The primary efficacy endpoint for the study was 28-day all-cause mortality in the patients who received any amount of study medication with a confirmed baseline infection with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC microbiologically modified intent to treat (m-MITT) population). Among 128 patients in the CRABC m-MITT population, 125 patients who did not withdraw consent prior to assessment of survival status at Day 28 were assessed: 63 patients in the XACDURO group and 62 patients in the colistin group.

The demographic and baseline characteristics were comparable between treatment groups among 125 patients in the analysis: 74% male, 50% White, and 44% Asian; the mean age was 63 (±17) years. The majority of patients had pneumonia as the baseline infection (53% VABP and 43% HABP); 2% had bacteremia. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score at baseline was 17, and 26% of patients had an APACHE II score ≥ 20. At randomization, 64% of patients had been in the ICU ≥5 days, 26% of patients had been in the ICU for >14 days, and 75% were mechanically ventilated. Approximately 39% of patients had CLcr less than 90 mL/min at baseline. The mean duration of treatment was 9 days for the XACDURO group and 8 days for the colistin group.

Table 5 shows results for the primary endpoint of Day 28 all-cause mortality in the CRABC m-MITT population. XACDURO was non-inferior to colistin with regard to Day 28 all-cause mortality.

Clinical cure rates were also evaluated. Clinical cure was defined as complete resolution or significant improvement of signs and symptoms that were present at baseline and no new symptoms, such that no additional gram-negative antimicrobial therapy was warranted. Clinical cure rates in the CRABC m-MITT population at the Test of Cure (TOC) Visit that was 7 days (±2 days) after the end of treatment were 39/63 (61.9%) for XACDURO versus 25/62 (40.3%) for colistin.

16.1 How Supplied

XACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. XACDURO is supplied as a kit (NDC 68547-111-10) containing the following single-dose vials each containing sterile powder for reconstitution:

• 1 g sulbactam in one clear glass single-dose vial
• 1 g durlobactam in two amber glass single-dose vials (0.5 g durlobactam in each single-dose vial)

Stoppers are not made with natural rubber latex.

16.2 Storage and Handling

XACDURO vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F); brief exposure to 8°C to 15°C (46°F to 59°F) permitted [see USP Controlled Cold Temperature]. Do not freeze. Store prepared XACDURO solution in the refrigerator [see Dosage and Administration (2.6)].

Serious Allergic Reactions

Advise the patient, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask them about any previous hypersensitivity reactions to XACDURO (sulbactam and durlobactam), other beta-lactams (including cephalosporins) or other allergens [see Warnings and Precautions (5.1)].

Potentially Serious Diarrhea

Advise the patient, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including XACDURO. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell them to contact their healthcare provider [see Warnings and Precautions (5.2)].

Antibacterial Resistance

Patients should be counseled that antibacterial drugs, including XACDURO, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Patients should be told that the medication should be administered exactly as directed. [see Warnings and Precautions (5.3)].